title: Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults.
abstract: OBJECTIVE
  To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of short-term monotherapy with tenofovir alafenamide (TAF), a next-generation tenofovir (TFV) prodrug.
  
  
  METHODS
  A phase 1b, randomized, partially blinded, active- and placebo-controlled, dose-ranging study.
  
  
  METHODS
  Treatment-naive and experienced HIV-1-positive adults currently off antiretroviral therapy were randomized to receive 8, 25, or 40 mg TAF, 300 mg tenofovir disoproxil fumarate (TDF), or placebo, each once daily for 10 days.
  
  
  RESULTS
  Thirty-eight subjects were enrolled. Baseline characteristics were similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline to day 11 were observed for all TAF dose groups compared with placebo (P < 0.01), with a median decrease of 1.08-1.73 log10 copies per milliliter, including a dose-response relationship for viral load decrease up to 25 mg. At steady state, 8, 25, and 40 mg TAF yielded mean TFV plasma exposures [area under the plasma concentration-time curve (AUCtau)] of 97%, 86%, and 79% lower, respectively, as compared with the TFV exposures observed with 300 mg TDF. For 25 and 40 mg TAF, the mean intracellular peripheral blood mononuclear cell tenofovir diphosphate AUCtau was ∼7-fold and ∼25-fold higher, relative to 300 mg TDF.
  
  
  CONCLUSIONS
  Compared with 300 mg TDF, TAF demonstrated more potent antiviral activity, higher peripheral blood mononuclear cell intracellular tenofovir diphosphate levels, and lower plasma TFV exposures, at approximately 1/10th of the dose. This may translate into greater antiviral efficacy, a higher barrier to resistance, and an improved safety profile relative to TDF, supporting further investigation of TAF dosed once daily in HIV-infected patients.
authors.affiliation: Peter J. Ruane MD Inc, Los Angeles, CA 90036, USA. pjruane@lightsourcemedical.com
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ruane
authors.forename: Edwin
authors.initials: E
authors.lastname: DeJesus
authors.forename: Daniel
authors.initials: D
authors.lastname: Berger
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.forename: U Fritz
authors.initials: UF
authors.lastname: Bredeek
authors.forename: Christian
authors.initials: C
authors.lastname: Callebaut
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhong
authors.forename: Srini
authors.initials: S
authors.lastname: Ramanathan
authors.forename: Martin S
authors.initials: MS
authors.lastname: Rhee
authors.forename: Marshall W
authors.initials: MW
authors.lastname: Fordyce
authors.forename: Kitty
authors.initials: K
authors.lastname: Yale
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000409:Alanine; D044966:Anti-Retroviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010755:Organophosphates / Q000097:blood; D063065:Organophosphonates / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood*; D016037:Single-Blind Method; D018709:Statistics, Nonparametric; D000068698:Tenofovir / Q000031:analogs & derivatives; D019562:Viral Load; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents; D010755:Organophosphates; D063065:Organophosphonates; D012367:RNA, Viral; C583447:tenofovir diphosphate; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine